The 6-hydroxyethyl penam compound is represented by General Formula (2) below:
wherein R represents a hydrogen atom or a protective group for carboxylic acid, and X2 represents a halogen atom.
The 6-hydroxyethyl penam compound is an important intermediate for synthesizing carbapenem antibiotics, including thienamycin, which is widely used as an injection medicine (Non-Patent Document 1).
The 6-hydroxyethyl penam compound represented by General Formula (2) comprises an asymmetrical carbon on the penam ring at 6-position at which a hydroxyethyl group and a halogen atom are substituted. Therefore, in the production of 6-hydroxyethyl penam compound, a method that achieves excellent stereoselectivity is required. Various studies have been conducted regarding the process by which a 6-hydroxyethyl penam compound is derived from a compound, such as the halogeno penam compound represented by General Formula (1) below having a skeleton in which 6-position is substituted with a halogen atom:
wherein R and X2 are the same as above, and X1 represents a halogen atom.
For example, a method employing a Grignard reagent is proposed. Non-Patent Document 2 discloses a method using methylmagnesium bromide, and Patent Document 1 discloses a method using ethylmagnesium bromide.
However, in these methods, it is impossible to produce the 6-hydroxyethyl penam compound represented by General Formula (2) with a high selectivity. For example, in the method of Non-Patent Document 2, the stereoselectivity of the objective compound is only about 70% (objective compound:byproduct=230:96.5). In the method of Non-Patent Document 1, the stereoselectivity of the objective compound is only about 62% (see Comparative Example 1 described below).
[Patent Document 1]
Japanese Examined Patent Publication No. 1990-25914
[Non-Patent Document 1]
“Saishin Kouseizai Yoko” (Novel Antibiotic Booklet), 9th Edition, Katsuji SAKAI, page 92
[Non-Patent Document 2]
J. Org. Chem., 42, 2960 (1977)